Sturge-Weber Syndrome

A number sign (#) is used with this entry because of evidence that Sturge-Weber syndrome can be caused by somatic mosaic mutation in the GNAQ gene (600998) on chromosome 9q21.

Nonsyndromic port-wine stains (CMC; 163000) are also caused by somatic mosaic mutation in the GNAQ gene.

Description

Sturge-Weber syndrome is characterized by an intracranial vascular anomaly, leptomeningeal angiomatosis, most often involving the occipital and posterior parietal lobes. The most common symptoms and signs are facial cutaneous vascular malformations (port-wine stains), seizures, and glaucoma. Stasis results in ischemia underlying the leptomeningeal angiomatosis, leading to calcification and laminar cortical necrosis. The clinical course is highly variable and some children experience intractable seizures, mental retardation, and recurrent stroke-like episodes (review by Thomas-Sohl et al., 2004).

Clinical Features

The Klippel-Trenaunay-Weber syndrome (149000) is sometimes associated with SWS (see Bonse, 1951 and Nonnenmacher, 1955).

Debicka and Adamczak (1979) described Sturge-Weber syndrome in father and son, both of whom had, in addition to trigeminal angiomatous nevi, evidence of central nervous system involvement. The son had congenital glaucoma and the father had simple glaucoma. All manifestations were more pronounced in the son.

Sujansky and Conradi (1995) reviewed the outcome in 52 adults, aged 18 to 63 years, ascertained through the Sturge-Weber Foundation, and surveyed by written questionnaires, telephone interviews, and review of medical records. The distribution of port-wine stains (cranial 98%, extracranial 52%) and the prevalence of glaucoma (60%), seizures (83%), neurologic deficit (65%), and other complications were established. The age of onset of glaucoma varied from birth to 41 years and the age of onset of seizures from birth to 23 years. In those with and those without seizures, the prevalence of developmental delay (43% vs 0%), emotional and behavioral problems (85% vs 58%), special education requirements (71% vs 0%), and employability (46% vs 48%) was determined. Overall, 39% were financially self sufficient. Ten participants produced 20 liveborn offspring; 17 were healthy, and tuberous sclerosis, a cafe-au-lait spot, and a 'birthmark' were found in 1 child each.

Griffiths et al. (1996) found enlargement of the choroid plexus in the hemisphere affected with SWS in an MRI study of 15 children.

Another ocular manifestation of SWS is circumscribed choroidal hemangioma (CCH). Porrini et al. (2003) found that photodynamic therapy in 10 SWS patients with symptomatic CCH of the posterior pole resulted in improved visual acuity in all.

Quigg et al. (2006) presented photographs and brain images of an infant with SWS. The patient had a bilateral ophthalmologic port-wine stain in the trigeminal distribution and an extracranial nevus on the chest. Bilateral or more lower facial involvement occurs in 15% of patients with SWS. Head radiograph showed gyral calcifications of a subarachnoid angioma across most of the right hemisphere. Quigg et al. (2006) noted that leptomeningeal involvement often leads to hemiparesis, mental retardation, and epilepsy.

Among 21 children aged 18 months to 10 years with SWS and unilateral cerebral hemispheric involvement, Juhasz et al. (2007) found a significant correlation between decreased white matter volume in the affected hemisphere and cognitive decline. There was no correlation with gray matter volume. The authors hypothesized that white matter abnormalities in SWS may be due to hypoxic injury secondary to impaired venous drainage. Cognitive impairment was not related to seizures.

Hall et al. (2007) reported 6 patients with phakomatosis pigmentovascularis type II, consisting of nevus flammeus and mongolian spots; 2 patients were diagnosed with Klippel-Trenaunay syndrome, and 3 had features consistent with both Klippel-Trenaunay and Sturge-Weber syndromes. There were 4 patients with macrocephaly and 1 with microcephaly; 4 patients had CNS abnormalities, including 3 with hydrocephalus, 1 with Arnold-Chiari malformation, and 1 with polymicrogyria; 3 patients had mental retardation; and 1 patient had seizures. Hall et al. (2007) suggested that in the presence of persistent, extensive, and aberrant mongolian spots, the vascular abnormalities of Klippel-Trenaunay and Sturge-Weber syndromes carry a worse prognosis.

Biochemical Features

Using PET scans to correlate cortical glucose hypometabolism with clinical features in 13 children with unilateral cerebral SWS, Lee et al. (2001) found that the extent and degree of glucose asymmetry were sensitive markers of seizure severity and cognitive decline. Both seizure frequency and lifetime number of seizures showed a positive correlation with area of mildly asymmetric cortical hypometabolism, suggesting a nociferous effect on the remainder of the brain. Patients with a higher IQ had a larger area of severely asymmetric cortical metabolism, suggesting early functional reorganization.

Pathogenesis

Tyzio et al. (2009) reported the histopathologic findings of brain tissue derived from 4 pediatric SWS patients who underwent surgical hemispherectomy for refractory epilepsy at a mean age of 10.5 months. There were changes in cortical layering, with neuronal degeneration and loss, with many neurons containing perinuclear chromatin aggregates and nuclear condensation. Gray matter contained irregular vascular dilatations and calcifications. Neurons had small soma and dendrites that were tiny and poorly branched, reflecting a reduced degree of neuronal maturation. These findings were consistent with an ischemic/hypoxic process. Electrophysiologic studies showed that neurons had spontaneous activity and a more depolarized resting membrane potential, indicative of increased excitability. Studies of GABA channels indicated that they had an inhibitory and anticonvulsive effect on SWS neurons.

Inheritance

Unlike the other phacomatoses, including tuberous sclerosis (see 191100), neurofibromatosis (see 162200), and von Hippel-Lindau disease (193300), no clear evidence of heredity has been discovered in SWS.

Happle (1987) suggested that somatic mosaicism underlies the pathogenesis of lesions in SWS and certain other disorders.

In 4 patients with SWS, Huq et al. (2002) compared the chromosomes in cells from affected areas with those from unaffected areas. In 1 patient, a paracentric inversion of chromosome 4q was present in 40% of cells cultured from leptomeningeal angiomatosis, but the inversion was not present in cells cultured from the patient's blood. In a second patient, approximately 50% of cells from a port-wine stain showed trisomy 10, whereas this abnormality was not present in the patient's blood or normal skin.

Comi et al. (2003) compared fibronectin gene and protein expression from port-wine-derived fibroblasts compared with that from normal skin-derived fibroblasts of 4 individuals with SWS. The gene expression of fibronectin was significantly increased in the SWS port-wine-derived fibroblasts compared with that of fibroblasts from SWS normal skin. Comi et al. (2003) concluded that the reproducible differences in fibronectin gene expression between the 2 sets of fibroblasts are consistent with the presence of a hypothesized somatic mutation underlying SWS.

Molecular Genetics

Shirley et al. (2013) performed whole-genome sequencing of DNA from paired samples of visibly affected and normal tissue from 3 SWS patients and identified 1 nonsynonymous somatic single-nucleotide variant in the GNAQ gene (R183Q; 600998.0001) that was present in all 3 affected samples and was not present in the normal-appearing samples. Screening of additional SWS patients as well as individuals with nonsyndromic port-wine stains (163000) revealed that all 9 SWS patients were positive for the R183Q mutation in port-wine-stained skin, 6 (86%) of 7 participants with SWS were negative for the mutation in visibly normal skin, and 12 (92%) of 13 participants with nonsyndromic port-wine stains were positive for the mutation. The mutation was also detected in brain samples from 15 (83%) of 18 SWS patients, whereas all 6 brain samples from normal controls were negative. Overall, 23 (88%) of 26 SWS patients were positive for the gain-of-function R183Q mutation in either port-wine-stained skin or brain tissue. Shirley et al. (2013) suggested that nonsyndromic port-wine stains may represent a late origin of the somatic GNAQ mutation in vascular endothelial cells, whereas in Sturge-Weber syndrome, the mutation may occur earlier in development, in progenitor cells that are precursors to a larger variety of cell types and tissues, leading to the syndromic phenotype. Five (0.7%) of 669 samples from the 1000 Genomes database were positive for R183Q; noting that the reported prevalence of port-wine stains is 0.3% to 0.5%, Shirley et al. (2013) hypothesized that the 0.7% prevalence in that database represented the occurrence of port-wine stains in the population.